Endothelin-1 in portal hypertension: The intricate role of hepatic stellate cells

Abstract

Portal hypertension is one of the most important cirrhosis-associated complications of chronic liver disease, leading to significant morbidity and mortality. After chronic liver injury, hepatic stellate cells reside in the perisinusoidal space activted and acquire a myofibroblast-like phenotype. The activated hepatic stellate cells act as both sources as well as the target for a potent vasoconstrictor endothelin-1. Activation of hepatic stellate cells plays a vital role in the onset of cirrhosis by way of increased extracellular matrix production and the enhanced contractile response to vasoactive mediators such as endothelin-1. In fibrotic/cirrhotic liver, activated hepatic stellate cells produce endothelin-1 leading to an imbalance between pro and antifibrotic factors responsible for enormous extracellular matrix synthesis. Thus, extracellular matrix deposition in the perisinusoidal space further augments liver stiffness and elevates the vascular tone and portal hypertension. Portal hypertension is a complex process modulated by several cell types like hepatic stellate cells, liver sinusoidal endothelial cells, Kupffer cells, injured hepatocytes, immune cells, and biliary epithelial cells. Therefore, targeting a single cell type may not be useful for regression of cirrhosis and portal hypertension. Nevertheless, numerous findings indicate that functionally liver sinusoidal endothelial cells and hepatic stellate cells closely regulate the sinusoidal blood flow via synthesis of several vasoactive molecules including endothelin-1, and hence targeting these cells with novel pharmacological agents may offer promising results. Impact statement Portal hypertension is pathologically defined as increase of portal venous pressure, mainly due to chronic liver diseases such as fibrosis and cirrhosis. In fibrotic liver, activated hepatic stellate cells increase their contraction in response to endothelin-1 (ET-1) via autocrine and paracrine stimulation from liver sinusoidal endothelial cells and injured hepatocytes. Clinical studies are limited with ET receptor antagonists in cirrhotic patients with portal hypertension. Hence, studies are needed to find molecules that block ET-1 synthesis. Accumulation of extracellular matrix proteins in the perisinusoidal space, tissue contraction, and alteration in blood flow are prominent during portal hypertension. Therefore, novel matrix modulators should be tested experimentally as well as in clinical studies. Specifically, tumor necrosis factor-α, transforming growth factor-β1, Wnt, Notch, rho-associated protein kinase 1 signaling antagonists, and peroxisome proliferator-activated receptor α and γ, interferon-γ and sirtuin 1 agonists should be tested elaborately against cirrhosis patients with portal hypertension.

Novel Nano-Based Drug Delivery Systems Targeting Hepatic Stellate Cells in the Fibrotic Liver

“…These signaling molecules from activated HSCs, act on themselves via an autocrine manner also activate other cells such as quiescent HSCs, hepatocytes, and LSECs via a paracrine manner. For instance, activated HSCs and LSECs communicate each other with ET-1, leading to portal hypertension [15]. Activated HSCs induce the proliferation and activation of quiescent HSCs by expressing PDGF and TGF-β, which increases the burden of ECM synthesis.…”

“…Increased intrahepatic resistance and portal hypertension are major complications of advanced fibrosis and cirrhosis. HSC activation and subsequent ET-1 release from myofibroblasts and LSECs cause portal hypertension [15]. The influence of angiotensin II receptor antagonist, i.e., valsartan, on portal hypertensiand hepatic fibrosis has been studied in hepatic cirrhotic patients [46,47].…”

“…VLL exhibits poteintal antifibrotic effects with PPAR-γ agonistic activity and prolonged delivery [50]. Nitric oxide is a potent vasodilator, and it was shown to inhibit HSC activation and regulate portal hypertension [15]. Therefore, nitric oxide (NO) donor molecule-based drug delivery systems have been developed.…”

Pathogenesis of Liver Fibrosis and Its TCM Therapeutic Perspectives

“…ET-1 is caused by the massive accumulation of extracellular matrix ECM activated by HSC and also stimulates proliferation and collagen synthesis by inducing contraction of activated HSC, which can act on LSEC in addition to HSC [ 108 ], and ET-1 can reduce the size and number of window pores in LSEC [ 30 ], which in turn can affect liver microcirculation. In CCL4-induced liver fibrosis, ET-1 expression was increased, suggesting that ET-1 could be a promising marker [ 109 ].…”

Methotrexate Toxicity: Molecular Mechanisms and Management

“…Following damage to the liver, injured hepatocytes discharge diverse pro-inflammatory markers, which convert inactive HSCs to an active state or generate phenotypes akin to myofibroblasts (MFBs). The triggered HSCs give rise to the marked production of the extracellular matrix that generates liver fibrosis [40][41]. Furthermore, the accrual of MTX-PG within the liver tissue stimulates MTHFR, which, in turn, precipitates raised titres of intracellular and serum homocysteine [42][43].There is an association between the accumulation of intracellular homocysteine levels generated by MTX-PGs and the progression of hepatic oxidative stress, and inflammatory and fibrotic processes [44][45].…”